Postnatal regulation of B-1a cell development and survival by the CIC-PER2-BHLHE41 axis

B-1 cell development mainly occurs via fetal and neonatal hematopoiesis and is suppressed in adult bone marrow hematopoiesis. However, little is known about the factors inhibiting B-1 cell development at the adult stage. We report that capicua (CIC) suppresses postnatal B-1a cell development and survival. CIC levels are high in B-1a cells and gradually increase in transitional B-1a (TrB-1a) cells with age. B-cell-specific Cic-null mice exhibit expansion of the B-1a cell population and a gradual increase in TrB-1a cell frequency with age but attenuated B-2 cell development. CIC deficiency enhances B cell receptor (BCR) signaling in transitional B cells and B-1a cell viability. Mechanistically, CIC-deficiency-mediated Per2 derepression upregulates Bhlhe41 levels by inhibiting CRY-mediated transcriptional repression for Bhlhe41, consequently promoting B-1a cell formation in Cic-null mice. Taken together, CIC is a key transcription factor that limits the B-1a cell population at the adult stage and balances B-1 versus B-2 cell formation. [Display omitted] •CIC deficiency increases B-1a cell population at the expense of B-2 subsets•The frequency of TrB-1a cells gradually increases in Cic mutant mice with age•CIC deficiency enhances BCR signaling and B-1a cell viability•The CIC-PER2-BHLHE41 axis regulates B-1a cell development and survival Hong et al. show that CIC is a transcriptional repressor inhibiting B-1a cell formation during postnatal life. CIC levels gradually increase in TrB-1a cells with age, thereby inhibiting B-1a cell differentiation at the adult stage. CIC suppresses BHLHE41, a transcription factor promoting B-1a cell formation, by repressing Per2 expression.